Background The α1‐adrenoceptor agonist, phenylephrine, is used at high concentrations as a mydriatic agent and for the treatment of nasal congestion. Among its adverse side‐effects transient burning sensations are reported indicating activation of the trigeminal nociceptive system. Methods Neuropeptide release, calcium imaging and meningeal blood flow recordings were applied in rodent models of meningeal nociception to clarify possible receptor mechanisms underlying these pain phenomena. Results Phenylephrine above 10 mM dose‐dependently released calcitonin gene‐related peptide (CGRP) from the dura mater and isolated trigeminal ganglia, whereas hyperosmotic mannitol at 90 mM was ineffective. The phenylephrine‐evoked release was blocked by the transient receptor potential vanilloid 1 (TRPV1) antagonist BCTC and did not occur in trigeminal ganglia of TRPV1‐deficient mice. Phenylephrine at 30 mM caused calcium transients in cultured trigeminal ganglion neurons responding to the TRPV1 agonist capsaicin and in HEK293T cells expressing human TRPV1. Local application of phenylephrine at micromolar concentrations to the exposed rat dura mater reduced meningeal blood flow, whereas concentrations above 10 mM caused increased meningeal blood flow. The flow increase was abolished by pre‐application of the CGRP receptor antagonist CGRP8‐37 or the TRPV1 antagonist BCTC. Conclusions Phenylephrine at high millimolar concentrations activates TRPV1 receptor channels of perivascular afferents and, upon calcium inflow, releases CGRP, which increases meningeal blood flow. Activation of TRPV1 receptors may underlie trigeminal nociception leading to cranial pain such as local burning sensations or headaches caused by administration of high doses of phenylephrine. Significance Phenylephrine is used at high concentrations as a mydriaticum and for treating nasal congestion. As adverse side‐effects burning sensations and headaches have been described. Phenylephrine at high concentrations causes calcium transients in trigeminal afferents, CGRP release and increased meningeal blood flow upon activation of TRPV1 receptor channels, which is likely underlying the reported pain phenomena.

Background Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. Methods To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes. Findings We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity. Interpretation Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule. Funding This study was funded in part by the DFG, the BMBF, the Academy of Finland, the NIH, the Japanese Society of Clinical Neuropsychopharmacology, the Ministry of Education of the Russian Federation, and the European Community.

Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signaling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress the murine Nos1ap isoform in the hippocampus of mice. We investigated these mice for changes in gene expression, electrophysiology, neuronal morphology, and relevant behavioral phenotypes. We found that overexpression of hippocampal Nos1ap markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density and changed dendritic spine morphology without affecting basic synaptic signaling properties at CA1 synapses. At the behavioral level, we observed an impairment in social interaction and social memory, as well as decreased spatial working memory capacity. Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule.